It is well accepted that an effective and safe vaccine against HIV-1is of vital importance to stem the global AIDS pandemic, especially against HIV clade C, and that such a vaccine should generate both cellular and humoral immunity, including neutralizing antibody responses. The overall goal of Project 3 is to test a novel vaccine strategy to broaden nAb responses by a process termed SEquential Editing and Focusing of Antibody Responses (SEEFAR). We will combine the use of Env immunoqens deleted in hvpervariable regions that prevent immune recognition of conserved epitopes. with sequential immunization using Env immunoaens from different virus strains that, by definition, share only conserved epitopes. The SEEFAR concept will first be tested in rabbits and then incorporated into a multigenic, bimodal vaccine strategy that will be tested in a highly-relevant model system of simian/human immunodeficiency virus (SHIV) clade C mucosal challenge of rhesus macaques. Specific Aim 1a) To test the immunogenicitv of multiply V-loop deleted clade C Envs in rabbits. Specific Aim 1b) To test the SEEFAR concept with multiply V-loop deleted clade C Envs for its ability to induce broadly reactive nAb responses in rabbits. Specific Aim 2. To test the immunogenicitv and efficacy of a multiqenic prime/boost regimen in juvenile macaques against intrarectal challenge with SHIV-1157ipd3N4. Priming will be with replication-competent adenovirus vectors that encode clade C env, SIV gag and SIV nef;boosting will be with SIV Gag-Pol particles, Nef and different V loop-deleted clade C Envs as a direct test of our SEEFAR concept. Specific Aim 3. To test the immunogenicitv and efficacy of a multigenic prime/boost regimen in juvenile macaques against intrarectal challenge with a fully heterologous SHIVenvCd. The vaccination procedure of Specific Aim 2 will be followed and animals challenged with a fully heterologous challenge virus utilizing a SIVsmeE543-3 backbone and an HIV clade Cenv. Specific Aim 4. To test the immunogenicitv and efficacy of a prime/boost vaccine regimen in infant macaques against multiple, low-dose oral challenge with pathogenic SHIVenvC. In using our rhesus macaque/SHIV challenge model system to test SEEFAR, the data from the proposed studies will provide important new information to designing a safe and effective AIDS vaccines, especially against HIV clade C transmission to infants.